title: Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation.
abstract: OBJECTIVE
  The use of livers from donors after cardiac arrest (DCD) is increasing in many countries to overcome organ shortage. Due to additional warm ischemia before preservation, those grafts are at higher risk of failure and bile duct injury. Several competing rescue strategies by machine perfusion techniques have been developed with, however, unclear effects on biliary injury. We analyze the impact of an end-ischemic Hypothermic Oxygenated PErfusion (HOPE) approach applied only through the portal vein for 1h before graft implantation.
  
  
  METHODS
  Rat livers were subjected to 30-min in situ warm ischemia, followed by subsequent 4-h cold storage, mimicking DCD-organ procurement and conventional organ transport. Livers in the HOPE group underwent also passive cold storage for 4h, but were subsequently machine perfused for 1h before implantation. Outcome was tested by liver transplantation (LT) at 12h after implantation (n=10 each group) and after 4 weeks (n=10 each group), focusing on early reperfusion injury, immune response, and later intrahepatic biliary injury.
  
  
  RESULTS
  All animals survived after LT. However, reperfusion injury was significantly decreased by HOPE treatment as tested by hepatocyte injury, Kupffer cell activation, and endothelial cell activation. Recipients receiving non-perfused DCD livers disclosed less body weight gain, increased bilirubin, and severe intrahepatic biliary fibrosis. In contrast, HOPE treated DCD livers were protected from biliary injury, as detected by cholestasis parameter and histology.
  
  
  CONCLUSIONS
  We demonstrate in a DCD liver transplant model that end-ischemic hypothermic oxygenated perfusion is a powerful strategy for protection against biliary injury.
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB and Liver Transplantation Center, University Hospital Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlegel
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
authors.forename: Philipp
authors.initials: P
authors.lastname: Dutkowski
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000293:injuries*; D003080:Cold Temperature; D004195:Disease Models, Animal; D006085:Graft Survival; D006323:Heart Arrest; D022781:Hepatocytes / Q000473:pathology; D007728:Kupffer Cells / Q000473:pathology; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D010100:Oxygen; D010477:Perfusion / Q000379:methods; D051381:Rats; D011914:Rats, Inbred BN; D015427:Reperfusion Injury / Q000517:prevention & control; D009927:Tissue and Organ Procurement; D016896:Treatment Outcome; D052096:Warm Ischemia / Q000009:adverse effects
chemical_list: D010100:Oxygen
keywords: 8-OHdG; 8-hydroxydesoxy-guanosin; Biliary injury; CD154; CD28; CD40; CD68; CD80; DAMPs; DCD; DCD liver; ELISA; FACS; H&E; HMGB1; HOPE; Hypothermic oxygenated perfusion; IC; IL-17; IL-2; Immune response; Liver transplantation; MPT; ROS; SECs; TLR-4; TNF-α; TUNEL; Toll-like receptor 4; alpha smooth muscle actin; cluster of differentiation 40; cluster of differentiation 68; cluster of differentiation 80; co-stimulatory protein 28; co-stimulatory protein 40 ligand; damage associated molecular pattern signalling; donation after cardiac death; enzyme-linked immunosorbent assay; fluorescence-activated cell sorting; haematoxylin and eosin; high mobility group box-1 protein; hypothermic oxygenated perfusion; interleukin-17; interleukin-2; ischemic cholangiopathy; mitochondrial permeability pore; reactive oxygen species; sinusoidal endothelial cells; terminal deoxynucleotidyltransferase assay; tumor necrosis factor alpha; α-SMA